Humoral and cellular responses raised against the human HER2 oncoprotein are cross-reactive with the homologous product of the neu proto-oncogene, but do not protect rats against B104 tumors expressing mutated neu

Taylor, Peter; Gerder, Marlene; Moros, Zoila; Feldmann, Marc

doi:10.1007/s002620050268

Cited by 11 publications

(10 citation statements)

References 24 publications

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“…In a different type of HER-2-positive tumor, ovarian carcinoma, it was shown that in vitro co-culture of HLA-A2 ϩ , HER-2 ϩ tumor cells with HLA-A2-restricted anti-HER-2 cytotoxic T lymphocytes leads to the appearance of escape variants with reduced HLA-A2 expression (Kono et al, 1997). The immune reactivity against neu and HER-2 are very similar, in fact cross-reactive humoral and cellular responses have been documented (Taylor et al, 1996). Together with our results on MHC class I loss in murine transgenic tumors, these data suggest that the relationship between HER-2 overexpression and MHC class I loss may also be worth investigating in human breast cancer.…”

Section: Mhc Class I Induction By Ifn-␥ In Vitromentioning

confidence: 99%

Down regulation of major histocompatibility complex class I expression in mammary carcinoma of HER-2/neu transgenic mice

et al. 1998

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Transgenic mice carrying the HER‐2/neu proto‐oncogene under tissue‐specific transcriptional control of a mammary tumor virus long terminal repeat (Tg‐MMTVneu mice) spontaneously develop mammary carcinomas. HER‐2/neu is a tumor antigen that can be recognized by cytotoxic T lymphocytes if tumor cells present the appropriate major histocompatibility complex (MHC) class I glycoproteins. The purpose of this work was to assess whether mammary carcinomas arising in Tg‐MMTVneu mice correctly expressed MHC (H‐2q) class I gene products. We analyzed by flow cytometry 51 primary tumors from 19 transgenic mice. About one‐half of the tumors showed a reduced expression of class I antigens. All tumors were highly positive for membrane neu. Some mice had multiple mammary carcinomas with widely different MHC expression levels, and most mice had at least one tumor with a low expression. Treatment with γ‐interferon of carcinoma cells cultured in vitro induced a strong re‐expression of H‐2q antigens. Our results suggest that the immune response activated in vivo by HER‐2/neu‐positive tumors can lead to the emergence of escape variants characterized by a down‐regulation of MHC class I products. Int. J. Cancer 77:937–941, 1998.© 1998 Wiley‐Liss, Inc.

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Section: Mhc Class I Induction By Ifn-␥ In Vitromentioning

confidence: 99%

Down regulation of major histocompatibility complex class I expression in mammary carcinoma of HER-2/neu transgenic mice

et al. 1998

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“…Immunization of rats with human p NeuECD in CFA did elicit an immune response to the rat HER-2/ neu antigen (rNeu) but did not protect against tumor formation of rNeu-expressing tumors [41]. The same lack of antitumor response was seen in mice vaccinated with human p NeuECD using montaide 720 as an immunoadjuvant [42].…”

Section: Discussionmentioning

confidence: 99%

Virosomes as new carrier system for cancer vaccines

Schwaninger

Waelti

Zajac

et al. 2004

Cancer Immunol Immunother

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HER-2/neu, a tumor-associated antigen (TAAg), plays a critical role in oncogenesis of various tumor types, and its selective overexpression by malignant tumor cells makes it an ideal target for immunotherapy. A prerequisite for clinical vaccines is the construction of safe and highly immunogenic reagents able to generate efficient immune responses against TAAg. Previous protein vaccines, consisting of the extracellular domain of HER-2/neu (p NeuECD ), were shown to elicit an immune response that did not provide protection from transplantable tumors expressing HER-2/neu. Here we showed that virosomes, which consist of reconstituted viral envelopes without viral genetic material, can act as a carrier and an adjuvant for a truncated protein p NeuECD . Mice vaccinated with p NeuECD either encapsulated in virosomes or bound to the virosomal membrane (Vir-p NeuECD ), generated rNeu-specific humoral and cytotoxic immune responses. In addition, Vir-p NeuECD induced significant tumor rejection and additionally did not lead to delayed tumor formation when compared with free p NeuECD in complete Freund's adjuvant. There was no difference between the virosomal constructs. Taken together these results suggest that virosomes, as clinically approved safe vaccines, can be used to elicit both humoral and cellmediated responses against TAAg and induce tumor rejection. Our model is providing important preclinical data to design human vaccination trials for patients with tumors overexpressing HER-2/neu, either as a primary vaccination or as a boost in combination with other vaccines in a context of an adjuvant treatment plan.

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“…The intracellular domain of Her2/neu produced in E. coli has been shown to partially inhibit the growth of cancer cells [10]. However the extracallular fragment produced in various transfected cell lines such as DHFR/G8, BHK/erbB2 and L cells which confer normal mammalian glycosylation and not mannosylation, could not confer any protection against growing tumors [9,11]. In contrast, when the ECD/Her2 was fused to cytokines like GM-CSF [12], or combined with anti-Her2/neu IgG3 antibodies fused to cytokines IL-2, IL-12 and GM-SCF [11], both humoral and cell-mediated responses against Her2/neu were observed.…”

Section: Discussionmentioning

confidence: 99%

“…DNA- and peptide-based vaccines were able to break tolerance and generate tumor antigen-specific immunity in animal models [5-8]. However, when the extracellular domain of the Her2/neu protein, produced in cell lines which confer normal mammalian glycosylation, was used as a vaccine, it could not confer protection against Her2/neu overexpressing tumors [9-11]. An effective immune response was elicited only when ECD/Her2 was fused to cytokines [12] or combined with antibodies fused to cytokines [11].…”

Section: Introductionmentioning

confidence: 99%

The mannosylated extracellular domain of Her2/neu produced in P. pastorisinduces protective antitumor immunity

et al. 2009

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BackgroundHer2/neu is overexpressed in various human cancers of epithelial origin and is associated with increased metastatic potential and poor prognosis. Several attempts have been made using the extracellular domain of Her2/neu (ECD/Her2) as a prophylactic vaccine in mice with no success in tumor prevention.MethodsThe extracellular domain of Her2/neu (ECD/Her2) was expressed in yeast P. pastoris, in a soluble highly mannosylated form. The immune response of the immunization with this recombinant ECD/Her2 was analyzed using immunoprecipitation and western blot analysis, proliferation and cytotoxicity assays as well as specific tumor growth assays.ResultsMannosylated ECD/Her2 elicited a humoral response with HER2/neu specific antibodies in vaccinated mice, which were able to reduce the proliferation rate of cancer cells in vitro. Moreover, it elicited a cellular response with Her2/neu-specific CTL capable of lysing tumor cells, in vitro. When immunized Balb/c and HHD mice were challenged with Her2/neu-overexpressing cells, tumor growth was inhibited.ConclusionHere we report on the efficacy of the extracellular domain of human Her2/neu produced in yeast P. pastoris, which confers mannosylation of the protein, to act as a potent anti-tumor vaccine against Her2/neu overexpressing tumors. Specific cellular and humoral responses were observed as well as efficacy.

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Humoral and cellular responses raised against the human HER2 oncoprotein are cross-reactive with the homologous product of the neu proto-oncogene, but do not protect rats against B104 tumors expressing mutated neu

Abstract: Humoral and cellular responses raised against the human HER2 oncoprotein are cross-reactive with the homologous product of the neu proto-oncogene, but do not protect rats against B104 tumors expressing mutated neu

Cited by 11 publications

References 24 publications

Down regulation of major histocompatibility complex class I expression in mammary carcinoma of HER-2/neu transgenic mice

Down regulation of major histocompatibility complex class I expression in mammary carcinoma of HER-2/neu transgenic mice

Virosomes as new carrier system for cancer vaccines

The mannosylated extracellular domain of Her2/neu produced in P. pastorisinduces protective antitumor immunity

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